: A significant collection of very large synthetic combinatorial peptide libraries, currently available at the investigator organization, will be used to identify arrays of peptide ligands specific for T cell clones of clinical relevance in various animal models of autoimmune disease. This technology has been used to screen dozens of human and murine CD4+ and CD8+ T cell clones of known and unknown specificity to identify agonists and antagonists having a broad range of activities on these clones. The overall goals of this research program are two-fold. First, to continue ongoing studies with peptide mimics of a model "academic" antigen system to gain a better understanding of various aspects of immune regulation, including certain details of TCR/peptide/MHC molecular interactions in the activation or inhibition of T cell responses at the clonal level in culture, TCR usage, and requirements for immunogenicity in vivo. A large panel of peptides of a model antigen system, pigeon cytochrome c, having a wide range of proliferative activity for a clonotypic population of murine T cells has been generated. It is important to relate the functional activity of these peptide sequences to physical binding properties in peptide/MHC and TCR/peptide/MHC interactions, requirements for co-stimulation molecules and the cytokine profile consequence following stimulation in vitro. In addition, it is important to relate the functional activity of this panel of peptides to the numbers of cells activated and the cytokine response profiles following in vivo immunization. Secondly, these studies will be extended to clinically relevant animal models of autoimmune disease to better understand the basis for T cell activation in immunogenicity and the onset of pathogenicity in vivo. Further knowledge in these areas is directly relevant to the identification and design of antigens for use as peptide and peptidomimetic vaccines for up-regulating immune responses in cancer and infectious disease and down-regulating immune responses in autoimmune disease.